1. Field of the Invention
The present invention relates to an stable injection formulation containing paclitaxel.
2. Description of the Prior Art
Paclitaxel is a diterpenoid compound which is widely used as an antineoplastic agent for the treatment of the breast and ovarian cancers. Also, the clinical tests of the paclitaxel for the other kinds of cancers are presently carried out in several countries. However, because of the extraordinary low solubility of the paclitaxel in water and in the pharmaceutically acceptable solvents (see, Flora K. P. et al, NCI Investigational Drugs Chemical Information, NCI, pp218(1992), the paclitaxel is limited in its formulation.
Cremophor EL, sold by BASF, is typically used as a solubilizer for the paclitaxel and is a condensation product of ethylene oxide and castor oil. This solubilizer is known to cause a reaction, such as a hyperallergic side reaction, when administered to patients. See, Alka-On Yuksel. H., et al, Pharmaceutical Research 11, 206(1994). Moreover, the injection formulation containing such a solubilizer has less dilution stability, when the formulation is diluted with saline or an aqueous dextrose solution. See, Mead Johnson Oncology (1993). The paclitaxel injection formulation exhibits instability over extended periods of time if an adequate pretreatment of the solubilizer is not foreseen. See, U.S. Pat. No. 5,504,102. A specially designed in-filter-infusion system is thus recommended for the administration of the injection formulation. See, Mead Johnson Oncology (1993).
Meanwhile, the commercial formulation presently available contains paclitaxel 30 mg/1 vial(5 ml), Cremophor EL 35.527 mg/ml and anhydrous ethanol 49.7 vol %.
As a result, although the paclitaxel is among the antineoplastic agents which are most widely used as the injection formulation, it has very low solubility in water or other solvents. Therefore, the solubilizers capable of being used for formulating the paclitaxel into the injection formulation are very limited.